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Late-onset leanness in mice with targeted ablation of melanin concentrating hormone neurons
Tamar Alon1, Jeffrey M Friedman
1Laboratory of Molecular Genetics, The Rockefeller University, New York, New York 10021, USA.
Abstract:
The observation that loss of orexin (hypocretin) neurons causes human narcolepsy raises the possibility that other acquired disorders might also result from loss of hypothalamic neurons. To test this possibility for body weight, mice with selective loss of melanin concentrating hormone (MCH) neurons were generated. MCH was chosen to test because induced mutations of the MCH gene in mice cause hypophagia and leanness. Mice with ablation of MCH neurons were generated using toxin (ataxin-3)-mediated ablation strategy. The mice appeared normal but, after 7 weeks, developed reduced body weight, body length, fat mass, lean mass, and leptin levels. Leanness was characterized by hypophagia and increased energy expenditure. To study the role of MCH neurons on obesity secondary to leptin deficiency, we generated mice deficient in both ob gene product (leptin) and MCH neurons. Absence of MCH neurons in ob/ob mice improved obesity, diabetes, and hepatic steatosis, suggesting that MCH neurons are important mediators of the response to leptin deficiency. These data show that loss of MCH neurons can lead to an acquired leanness. This has implications for the pathogenesis of acquired changes of body weight and might be considered in clinical settings characterized by substantial weight changes later in life.
Insights
Loss of melanin concentrating hormone (MCH) neurons causes acquired leanness in mice. Ablating MCH neurons also improved obesity and related conditions in leptin-deficient mice.
Area of Science:
- Neuroscience
- Endocrinology
- Metabolism
Background:
- Loss of orexin (hypocretin) neurons is linked to narcolepsy.
- Hypothalamic neurons play a role in regulating body weight.
- Melanin concentrating hormone (MCH) gene mutations in mice cause leanness.
Purpose of the Study:
- To investigate if loss of hypothalamic MCH neurons causes acquired changes in body weight.
- To determine the role of MCH neurons in obesity secondary to leptin deficiency.
Main Methods:
- Generated mice with selective loss of MCH neurons using a toxin-mediated ablation strategy.
- Studied body weight, body length, fat mass, lean mass, and leptin levels over 7 weeks.
- Generated mice deficient in both leptin and MCH neurons to assess MCH neuron role in leptin deficiency-induced obesity.
Main Results:
- Mice with MCH neuron ablation exhibited reduced body weight, length, fat mass, lean mass, and leptin levels.
- Leanness in these mice was associated with reduced appetite (hypophagia) and increased energy expenditure.
- Absence of MCH neurons ameliorated obesity, diabetes, and hepatic steatosis in leptin-deficient mice.
Conclusions:
- Loss of MCH neurons can lead to acquired leanness.
- MCH neurons are significant mediators in the response to leptin deficiency.
- These findings have implications for understanding acquired body weight changes and related clinical conditions.
